You'll find hundreds of files on cleft lip, cleft palate here on

This one is about: Smoking and Oral Clefts

(c) 1996 Wide Smiles
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A March of Dimes California Report of research findings 

About one in four California women smokes during pregnancy. Past studies hinted that smokers' babies may be more likely to have cleft lip and/or cleft palate, but results have been mixed. This study by the California Birth Defects Monitoring Program is one of the first to consider the babies' genes as well as mother's smoking. Based on interviews with almost 1500 mothers, it includes four times more oral cleft cases than most previous studies on the subject. It also looks at smoke from multiple sources, including second hand smoke.


Mothers were asked about their smoking habits during the month before conception through the first three months of pregnancy. Those who smoked twenty or more cigarettes per day were more than two times as likely to have babies with cleft lip and/or cleft palate. Those who smoked less were about one and a half times as likely to have babies with oral clefts. For nonsmoking mothers, the effects of second hand smoke were not clear-cut: there was little, if any, increased risk. Father's smoking increased the risk for oral clefts only if the mother smoked too.


Are some infants genetically more susceptible to mother's smoking? We looked at a gene normally involved in development of the palate and mouth - the Transforming Growth Factor-alpha gene (TGFa). Blood tests determined which of several forms of the gene babies inherited. Infants with the A2 form of the TGFa gene were eight times as likely to have oral clefts if their mothers smoked. Those born to non-smoking mothers were at no greater risk. About one in seven babies carries the A2 form of the TGFa gene.


It was also observed that smoking increased the risk for clefts whether or not the babies had additional birth defects. The mother's age, race/ethnicity, or education did not significantly alter the effects of smoking. Using multivitamins did not mitigate the risk associated with smoking.


We do not know why a mother's cigarette smoking increases the risk for clefts in the developing fetus. Both carbon monoxide and nicotine - agents released through smoking - may lower the oxygen available to the fetus. Other components of cigarettes have been linked to birth defects in laboratory animals as well. We do not yet know why infants with the A2 form of the TGFa gene are more susceptible.


All cases were identified through ongoing surveillance by California Birth Defects Monitoring Program registry, an actively ascertained population-based database on children with birth defects. Specific study elements follow:

*Birth defects:
   Cleft lip or palate or both. Infants with the chromosome abnormalities
   trisomy 21 (Down Syndrome) or 45,X (Turner Syndrome) were excluded. A
   medical geneticist classified cases according to the cleft type and
   whether additional birth defects were present. 

   Mothers of infants or fetuses with clefts identified from 552,601
   monitored births in 1987-1989, and a randomly selected comparison group
   of mothers delivering infants without birth defects in the same years.
   Mothers of 731 oral cleft cases agreed to be interviewed (85% of those
   eligible.) Interviews also took place with 734 mothers in the comparison
   group (78% of those eligible.)

*Diagnostic information:
   Abstracted from hospital medical records, including surgical reports.

   Forty-minute telephone interviews in English or Spanish asking about
   environmental exposures during pregnancy.

*Cigarette smoke exposure:
   Mother's reported tobacco use. Each woman also was asked whether anyone
   smoked in her home or near her at work, school, or during other routine
   activities. She was asked how many cigarettes per day her baby's father
   smoked in the three months before and three months after conception.

*Gene type:
   Determined by analyzing DNA from residual newborn screening specimens;
   85% of children were genotyped.

---Reference for this report: GM Shaw, CR Wasserman, EJ Lammer, CD O'Malley, JC Murray, AM Basart and MN Tolarova. Orofacial clefts, parental cigarette smoking and transforming growth factor-alpha gene variants.
American Journal of Human Genetics 1996;5(3):551-561.

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